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JCAD JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY February 2018 • Volume 11 • Number 2
R E V I E W
controlled trial (RCT) investigating mulberry use
in pigmentary disorders. Alvin et al
11
conducted
a randomized, single-blind, placebo-controlled
trial investigating the safety and efficacy of 75%
mulberry extract oil versus placebo in treating
melasma. There was significant improvement
in the MASI score, average skin colorimeter
measurements, and The Melasma Quality of
Life Scale (MelasQOL) scores in the treatment
group.
10,11
Licorice Extracts. Glabridin, extracted
from the root of perennial herb Glycyrrhiza
glabra linneva, is the main licorice compound.
12
This ingredient has been shown to scavenge
ROS, inhibit UVB-induced pigmentation and
tyrosinase without affecting DNA synthesis,
and possess anti-inflammatory properties.
Glabridin has been shown in vitro to have a
skin lightening effect 16 times greater than
that of hydroquinone and might reduce UVB
pigmentation.
13,14
A single-center, double-blind
comparison clinical study with 18 patients
compared the efficacy of a hydroquinone-
free skin brightener, comprising several
ingredients, including glabridin, that target
different pathways in melanogenesis, to
4% hydroquinone (HQ) cream in reducing
ultraviolet-induced hyperpigmentation.
15
The skin brightener demonstrated significant
reductions in pigmentation compared to
baseline and produced greater increases in
L* brightness compared to HQ. In addition to
assessing in-vivo data, this study used an in-vitro
model called MelanoDerm™ Skin Model (MatTek
Corp., to assess the ability of this product to
reduce melanin production and distribution
compared to controls. In the MelanoDerm Skin
Model in-vitro portion, the test product resulted
in greater reduction in melanin as measured
by melanin content and histological staining
compared to the control.
15
Another single-
blinded study compared a cream containing
belides, emblica, and licorice applied twice
daily to HQ 2% applied nightly in melasma
patients of Fitzpatrick Skin Types I to IV after the
patients had 60 days of exclusive use of an sun
protection factor (SPF) 35 sunscreen. Although
depigmentation was noted in both groups,
there was no statistical difference between
them in the improvement of melasma.
16
Liquiritin, a flavonoid component of licorice,
has multiple depigmenting properties, including
dispersing melanin, reducing inflammation,
and reducing UVB erythema.
10
Amer et al
17
conducted a double-blind, controlled, split-face
study of 20 women with epidermal melasma.
Subjects applied 20% liquiritin cream on one
side of the face and a vehicle cream on the other
side twice daily for four weeks. The majority
treated with liquiritin showed an "excellent
response" compared to the control group, which
exhibited no response. In a RCT conducted by
Zubair et al
10
in epidermal melasma patients,
4% liquiritin was shown to be significantly more
effective than 2% liquiritin and HQ.
Lignin peroxidase. The enzyme lignin
peroxidase is derived from the tree fungus
Phanerochaete chrysosporium and acts by
oxidizing and breaking down melanin. In
decaying trees, lignin, which is structurally
similar to melanin, is broken down by lignin
peroxidase, resulting in decolorization.
18
Mauricio et al
18
conducted a randomized,
double-blind, controlled, paired, split-face,
single-center study of 51 Asian female patients.
Lignin peroxidase cream was applied on one
side of the face and either 2% HQ or placebo
was applied on the other. The primary outcome
variable was reduction in the melanin index
with a sin colorimeter (Mexameter). Lignin
peroxidase cream had a significantly more rapid
and observable skin-lightening effect than
placebo and 2% HQ. A more recent randomized
paired, controlled, split-face study by Draelos et
al
19
investigated the pigment lightening efficacy
of lignin peroxidase in a cohort of women with
mild-to-moderate facial dyspigmentation. In
this 12 week study, Cohort 1 applied lignin
peroxidase to one side of the face twice daily
and nothing to the other side. Cohort 2 applied
twice-daily lignin peroxidase to one half of
the face and 4% HQ to the other half twice
daily. Subjects were assessed at baseline and
at Weeks 2, 8, and 12. Subject, investigator,
and dermospectrophotometer measurements
were obtained. In Cohort 1, lignin peroxidase
produced skin lightening superior to the control
group. In Cohort 2, lignin peroxidase produced
superior results in aesthetics when compared
to HQ including skin texture, lack of clarity and
radiance, roughness, and overall appearance.
However, parity was demonstrated between
both agents when evaluating skin lightening
efficacy. Lignin peroxidase does show promise
as a skin lightener based on the studies
available, but more studies are warranted.
Kojic Acid. Kojic acid (KA) is a metabolic
product of the fungal species Acetobacter,
Aspergillus, and Penicillium. It acts as a ROS
scavenger, exhibits antioxidant properties,
and inhibits tyrosinase.
20
KA is used in several
cosmetic skin brighteners and is also used as a
food additive to prevent browning.
1,12
Over the
years, there have been mixed reports on the
efficacy of KA. Based on earlier work, KA as a
monotherapy has shown modest effectiveness,
but it has been shown to be more beneficial
in combination with other ingredients. KA
stable derivatives increase skin penetration,
which offers better skin lightening. A recent
comparative study by Monteiro et al
21
evaluated
the efficacy of once-daily application of 4% HQ
and 0.75% KA cream, which contained 0.75%
KA and 2.5% vitamin C, in the treatment of
melasma. Sixty patients were enrolled in this
12-week study. The authors found that at Week
4, patients responded earlier to the HQ than
to the KA cream. However, at Week 12, HQ had
overall superiority in lightening compared to
the KA cream. Draelos et al
63
performed 12-
week, paired, double-blind study comparing a
preparation containing KA, emblica extract, and
glycolic acid to 4% HQ in 80 multiethnic patients
with facial dyschromia. Interestingly, the results
showed equivalent efficacy in skin lightening
capabilities between the two agents. Another
12-week simple, randomized, single-center,
single-blinded, parallel-group comparative
study comprising 80 subjects with melasma
compared the efficacy of KA 1% alone with
either 2% HQ or 0.1% betamethasone valerate,
and a combination of all these three agents.
Patients were assessed using the MASI score.
The study found that KA plus HQ was superior in
depigmenting when compared with the other
three groups.
22
With the conflicting studies
and lack of investigation exploring KA's role as
monotherapy, more clinical trials are warranted
Niacinamide. Niacinamide, an active
form of vitamin B3 (niacin) found in yeast
and root vegetables, is well known for its
role in enzymatic reaction.
12
It combats
hyperpigmentation by reversibly inhibiting
the transfer of melanosomes to epidermal
keratinocytes. A recent eight-week, prospective,
randomized, double-blind, vehicle-controlled
clinical study evaluated a combination of
niacinamide and tranexamic acid (TXA)
as a topical moisturizer in the treatment
of 42 Korean women with irregular facial
hyperpigmentation. This formulation was
significantly more effective in reducing the